Process for the preparation of pyrazinoylguanidines from a pyrazinoic azide and a guanidine



United States Patent ce 3,527,758 PROCESS FOR THE PREPARATION OF PYRAZINO- YLGUANIDINES FROM A PYRAZINOIC AZIDE AND A GUANIDINE Edward J. Cragoe, Jr., Lansdale, and James H. Jones,

Blue Bell, Pa., assignors to Merck & Co., Inc., a corporation of New Jersey N0 Drawing. Filed Apr. 13, 1967, Ser. No. 630,521 Int. Cl. C07d 51/76 US. Cl. 260-250 17 Claims This invention is concerned with a process for the preparation of pyrazinoylguanidines. In particular it is concerned with 3-aminopyrazinoic acid azides and the preparation of 3-aminopyrazinoylguanidines therefrom by a process which comprises the reaction of a novel pyrazinoic acid azide with a guanidine. The process can be represented by the following equation:

R /N\ NH:

'i' HsN-C- OONa LL wherein R represents:

(a) hydrogen,

(c) alkyl, preferably lower alkyl of from 1 to about 6 carbonatoms, either straight or branched chain, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched chained isomers, particularly methyl or ethyl,

(d) mononuclear aryl, especially phenyl, either unsub- 3,527,758 Patented Sept. 8, 1 970 stituted or substituted, especially with halo, such as chloro or bromo,

(e) mercapto,

('f) lower alkylthio of from 1 to about 5 carbon atoms,

particularly methyl, ethyl, or propylthio,

(g) phenyl-lower alkylthio wherein the alkyl moiety has from 1 to 3 carbons, such as benzylthio or phenethylthio or the like,

wherein R represents:

( 1) hydrogen,

(2) alkyl, preferably lower alkyl of from 1 to about 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl or hexyl, either straight or branched chain, particularly methyl or ethyl,

(3) lower alkenyl of from 2 to about 5 carbon atoms, particularly allyl, or propenyl,

and R represents:

(1) hydrogen,

(2) lower alkenyl of from 2 to about 5 carbon atoms, particularly allyl or propenyl,

(3) lower cycloal-kyl, having from 3 to about 8 carbon atoms, particularly cyclopropyl, cyclopentyl or cyclohexyl,

(4) mononuclear aryl, especially phenyl, either unsubstituted or substituted with for example lower alkyl having from 1 to 3 carbons or halo, especially chloro, bromo and fluoro,

(5) alkyl, preferably lower alkyl of from 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl or heXyl, either straight or branched chain, and either unsubstituted or substituted with, for example,

(a) hydroxy,

(b) di(lower alkyl)amino wherein each lower alkyl group has from 1 to about 4 carbon atoms, particularly methyl, or ethyl,

(0) lower cycloalkyl having from 3 to about 8 nuclear carbon :atoms, particularly cyclopropyl, cyclopentyl or cyclohexyl,

(d) mononuclear aryl, especially phenyl, either unsubstituted or substituted with, for example, lower alkyl having from 1 to 3 carbons, or halo, especially chloro, bromo or fiuoro,

(f) heterocyclic such as picolyl, rurfuryl, or the like,

3 (g) lower alkoxy of from 1 to about 4 carbon atoms, particularly methoxy or ethoxy, when R and R represent lower alkyl they can be linked together to form, with the nitrogen atom to which they are attached, a heterocyclic group, e.g., pyrrolidinyl, piperidino or the like;

R represents:

(a) halo, such as chloro or bromo,

('b) lower alkyl of from 1 to about 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl or hexyl, either straight or branched chain,

(c) mononuclear aryl, especially phenyl, either unsubstituted or substituted with for example halo, especially chloro or bromo;

R and R can be similar or dissimilar, and each represents:

(a) hydrogen,

(b) lower alkyl of from 1 to about 6 carbon atoms particularly methyl, ethyl, or propyl, or

(c) when both represent lower alkyl groups they can be linked together to form a cyclic structure with the nitrogens to which they are attached, particularly a Z-imidazolinyl or 3,4,5,6 tetrahydro 2 pyrimidinyl p;

R represents:

(a) hydrogen, (b) lower alkyl of from 1 to about 6 carbon atoms, particularly methyl, ethyl, or propyl, (c) substituted lower alkyl with substituents such as:

(l) aryl, such as naphthyl or phenyl, (2) substituted mononuclear aryl, such as with halogen, particularly chloro or fluoro, lower alkyl or lower alkoxy each having from I to about 3 carbon atoms, (3) heterocyclic substituents such as octahydro-lazocinyl, hexahydro-l-azepinyl or pyridyl, (4) hydroxyl, (d) mononuclear aryl, especially phenyl, either unsubstituted or substituted with, for example:

(1) lower alkyl of from 1 to about 3 carbons, such as methyl, ethyl or propyl, (2) lower alkoxy of from 1 to about 3 carbon atoms such as methoxy, ethoxy or propoxy, (3) halo, particularly chloro or fluoro; when R and R represent lower alkyl groups they may be linked either directly or through a hetero atom especially an O or N atom to produce a 5 to 8 membered ring, thus forming with the nitrogen atom to which they are attached rings such as l-pyrrolidinyl, piperidino, morpholino or the like.

oic acid azides were readily prepared and were indeed 7 much more reactive than the esters previously employed. The azides have the advantage of reacting rapidly with the guanidines including those that were previously found to be unreactive toward the ester or pyrazinoxazinone compounds and in the majority of cases to give, by virtue of the rapid rate of reaction, a better yield and purer product.

The process of this invention as shown by the equation III involves the treatment of a 3-amino-S-R-6-R -pyrazinoic acid azide with a 2-R -3-R -3R -guanidine to produce a 1 (3-amino 5-R-6-R pyrazinoyl) 2-tR -3-R -3-R guanidine. The pyrazinoic acid azide is usually added to an anhydrous solution of the guanidine, as the free base, in a hydroxylic solvent such as straight or branched chain or cyclic C alkanol such as methanol, ethanol, propanol, butanol, pentanol, hexanol, cyclopentanol, cyclohexanol, and the like or 2-alkoxyethanol or related solvents, preferably 2-propanol. The mixture then is heated at from steam bath temperature to about reflux temperature, conveniently the latter, for a few minutes to 5 to 6 hours, 30 minutes usually being suflicient. The end product, III, can then be isolated by known, conventional procedures such as by quenching the reaction mixture with an excess of ice water, usually about 2 volumes and collecting the precipitated solid by filtration or other convenient means and then drying. The solid then can be redissolved in water by the addition of a few drops of a mineral acid, the solution filtered and made acid with a slight excess of mineral acid, usually hydrochloric acid, and the precipitated product isolated by filtration and dried.

The pyrazinoic acid azide starting materials are not only useful as starting materials but some of them have useful biological properties as well. These compounds are obtained from the corresponding pyrazinoic acid hydrazides by diazotization with an alkali metal nitrite in strong acid medium. The alkali metal nitrite, usually sodium nitrite in water is added slowly, preferably below the surface, to a stirred solution of the hydrazide in dilute mineral acid, usually about 0.5 N hydrochloric acid, although concentrations of up to about 1 N sulfuric, hydrobromic or other mineral acids can be employed, at a temperature from ambient to about steam bath tem perature. The temperature employed is usually that required to dissolve the hydrazide. The acid azide precipitates from the reaction mixture. The azides can be purified and characterized if desired. However, they are in general unstable and tend to explode on heating. As a rule therefore they are dried carefully and used directly in the novel reaction of this invention without purification or characterization.

The pyrazinoic acid hydrazide starting materials are readily prepared by known methods and are described in Examples 1-36.

The pyrazinoylguanidine compounds prepared by the process of this invention are useful as they possess diuretic and natriuretic properties. They differ from most of the known, eifective diuretic agents; however, in that these compounds selectively enhance the excretion of sodium ions without causing an increase in potassium ion excretion. The potassium loss, which is caused by known 6 PREPARATION OF PYRAZINOIC ACID HYDRAZIDES Example 1.3-amino-5-diethylamino-fi-chloropyrazinoic acid hydrazide 5 p diuretics, often results in a severe muscular weakness. i ii g i fg g gp i gi Since the compounds prepared by the process of this ing g (1 g 3 12; 2 2525 6 3 fi fz l g f g g zzz g 32:23:: and the reaction mixture is refluxed for 4 hours. The ac 1v1 y, ey a e ths cc! 1; a (if ge t solvent is then removed in vacuo and the residue is As dluretlc agents ey can 6 or 6 washed out with water and dried to yield 9.0 g. (87%) of P rhypeftenslon and other dlseases known to be of 3-amino-5-diethylamino-6-chloropyrazinoic acid hydra- Tesponslve to thls f' P It also been found zide, melting at 137-140 C. After crystallization from other feature of this mventron that when co-admmrs- 2 1 the product melts at 445 Q tered with other diuretic agents known to enhance the Analysis,--Calcu1ated for C H ClN O (percent): C, elimination of potassium ions along with sodium ions, 41.79; H, 5. 84; N, 32.49. Found (percent): C, 42.00; the novel pyrazinoylguanidines of this invention will re- H, 6.05; N, 32.10. duce the excretion of potassium ions and thus overcome y emplflying Substantially the Same method de i this undesirable property of other diuretic agents. The lf 1, but SubSfitPtmg for l compounds prepared by the process of this invention, gfifii' 'gg x'ifigggggfifiggg?a g g gy g gggi r z es gj' f. are useful In r i Filth depicted in Table I, under starting materials, there are i; 51 a to zfi f e 31 potassmn produced according to equation I, the corresponding 3- e 0 dluretlcs el'wlse W0 cause to e armno-5-R-6-R -pyraz1no c acid hydrazldes, also shown nated. m Table Iunder the heading Products.

TABLE I N R NH: R N NH2 1. NHzNHa E 000011; R CONHNH Starting Material Product Analysis Calculated Found R R M.P;,C; Formula 0 H N c H N 02H5NH 01 163-70 C7H11C1N3O 36.45 4.30 36.44 36.71 4.37 36.7 GH =GHCHzNH- 01 153-60 CSHHCINGO 39.59 4.57 34.63 39.66 4.77 34. 6

4 /N CH3 CaHuNoO CH3 5--. N 01 134-6 C H ClN6O 39.27 5.36 34.35 39.36 5.51 34. 39

CH5 CH3\ 6 N 01 132-4 C3H13O1N3O 39.27 5.36 34.35 39.00 5.50 34.

7 O1OH:NH Cl 153-60 CmHmClzNuO 44.05 3.70 25.69 43.86 3.75 25. 61

CHI'I C12H13N50 9- CH3NH- Cl 257- CBHnClNaO Compound not purified 10. n-C4H5NH 01 162-5 C9H15C1N6O 41.73 5.34 32.49 42.10 6.0 32.6 11- n-O3H7-NH- 01 171.3 CsHiaClNaO 39.27 5.35 35.35 39.33 5.33 35.46 12-. HOCHzGHzNH- 01 134-5 C7H11C1N3O9 34. 03 450 34.07 3431 4.59 34.33 13- lit-OBEm- C1 CuHlsClNaO 14 l: -NH- 01 143-5 CmHmClNaO 44.36 5.53 31.05 44.52 5.71 30. 35

15 N-CHaCHzNH- 01 161-3 C9H13CIN7O 39.49 5.39 35.32 39.86 5.94 36. 04

16 0113s 01 240-2 C3H3C1N5OS 30.34 3.45 29.27 31.11 3.45 29.92 17 HS 01 218-20 O5HC1N5OS Compound not purified 1s -CHzNH- o1 071115011350 19. Ho 01 300 05H101N502 29.49 2.97 34.40 29.53 3.16 34.17 n-OsH7S- 01 166-3 csHnClNsOS 36.71 4.62 26.76 37. 03 4.44 27.15 CH Br 202-5 CaHaBlNaO 29.23 3.23 23.46 29.20 3.09 23.60

TABLE I-Continued Starting Material Product Analysis Calculated Found R R M.P., C. Formula C H N C H N Example 22 I NH o1 csrruomfio 2a om-Qcnmnc1 CmHmCINaO 24 Ol-NH o1 CuHmClNuO 25 Q-CHzCHzNH- o1 CHHUCINGO 26 CH3\ Q 1534 CraHmNeO 57. 34 5. 92 30. 86 57.77 5.81 30. 71

27 CFaCHzNH- Cl C7H9C1FNeO 28 C1 C11H12C1N7O N -OH2NH 20 C1 1l NflO2 W TCHzNH- 30 CgH5S-- Cl 196-9 C1H10C1N50S 33.94 4 07 28 27 34.13 3. 68 28.68 31 nC5H11S- Cl 255-7 (H01) CmHreClNfiOS-HCI 36.81 5.25 21 47 37.01 5.00 21.63

32 CH3 Cl CDHiaClNeO CH2=CHCH2 33 \N Cl CwHItC NoO 34 CE: 01 133-6 CQHlEClNBO 41.78 5. 84 32.49 41. 92 5.84 32.31

35 C1 CmHrzClNsOS CH2S 3G H B) C5HeBIN5O PREPARATION OF PYRAZINOYLGUANIDINES Example 37.(3,5-diamino 6 chloropyrazinoyl) guanidine hydrochloride Step A: Preparation of 3,S-diamino-6-chloropyrazinoic acid azide.To a stirred solution of 3,5-diamino-6-chloropyrazinoic acid hydrazide (10.0 g., 0.05 mole) in 0.5 N hydrochloric acid (350 ml.), maintained at 50-55 C., is added a solution of sodium nitrite (3.45 g., 0.05 mole) in water (20 ml.) over a period of minutes. The solid that separates is recovered by filtration, Washed Well with water and dried to yield 6.4 g. (60%) of 3,5-diamino-6- chloropyrazinoic acid azide, melting at 160 C. (explodes). The product is purified by dissolving in acetone and precipitating by the addition of water; however, the melting point remains unchanged.

Analysis-Calculated for C H CIN O (percent): C, 28.11; H, 1.89; N, 45.90. Found (percent): C, 28.35; H, 2.26; N, 45.71.

Step B: Preparation of (3,5-diamino-6-chloropyrazinoyl)guanidine hydrochloride.To a stirred solution of sodium (0.46 g., 0.02 g. atom) in 2-propanol ml.) is added guanidine hydrochloride (2.0 g., 0.002 mole) and the mixture is refluxed for 30 minutes then cooled and filtered to remove the precipitated sodium chloride. To the filtrate is added 3,5-diarnino-6-chloropyrazinoic acid azide (1.07 g., 0.005 mole) and the mixture is refluxed for 30 minutes, poured into ice water ml.) and the precipitated solid is recovered by filtration and dried. The solid is dissolved in water (50 ml.) by the addition of a few drops of hydrochloric acid and the solution is filtered. To the filtrate is added 6 N hydrochloric acid (10 ml.) and the solid that separates is recovered by filtration and dried to yield 0.4 g. (31%) of (3,5-diarnino-6-chloropyrazinoyl)guanidine hydrochloride dihydrate, melting at 285288 C. After careful purification the M.P. is 295 C.

Analysis.Calculated for CsHgClNqO'HClZHzO (percent): C, 23.85; H, 4.00; N, 32.45. Found (percent): C, 23.93; H, 4.40; N, 32.27.

The melting point of the free base is 240.5241.5 C., and that of the hydrochloride salt is 293.5 C.

Employing the method described in Example 37 but substituting for 3,S-diamino-6-chloropyrazinoic acid bydrazide used in Step A equimolar amounts of the 3-amino- 5-R-6-R -pyrazinoic acid hydrazides described in Table II, there are produced according to Equation II, the corresponding 3-amino-5-R-6-R -pyrazinoic acid azides which in most cases are not characterized. Then by employing the process of Step B, but substituting these acid azides for the 3,5-diamino-6-chloropyrazinoic acid azide and equimolar amounts of 2-R -3-R -3-R -guanidine identified in the table for the guanidine therein there are produced the 1-(3-amino-5-R-6-R -pyrazinoyl)-2-R -3-R -3- R -guanidines, also described in Table II.

|||||||||||||||||||||||||||| 1 mdfi aflm .1111... m m U "MHZ 41% .1.1-..111111111110. Q m 6 026 550 2 2m Y Q m 6 m om mo o za m o NE -OW O ZHO HH U md wdww 1 WO HHOOHH m m -O 4 Q m m m Q w MHHHHJ =2 m m m 6 mzz movo mo 6 E 1 3 m Hm m #0 m EEEM 11111.1.11.11.11.12 o zHo m o 5 3m 11 1 m m W 22mm w \hmnou 0 525 6 2+8 :2 m m m 6 I "m0 o zflo m o mfibdwm 1 HA HH m 0 2A mm -0.. EO HHO WHO 0:26 5 0 w BN 1 W m m 6 12/ EMU H H HH H 1 m mmfl mm mm n O w m o 3 wc 1 1 1 1 1 1: m Wm WM -O QW O 11111.10 1.111..111111.11n1hw 32 56 -Ofi0=w-=0 wTDw 1 m m m 6 O m 226 5 0 3 0mm 1 m m m 6 N A \Z w O Z EO W O m mmm 1 m m m 6 G Q MO 02 5 0 M78 2 m m m O 2/ HMO am za m o N8 2: m m m 6 ZNQ V Q ohzsosmuo 3km 1 HH m M 6 mZQlO 5 a a O od u 0 0 2 1% 3H EU in m a m EE M B S E 82 5 323m min mum o o m o 3min 5050 0 N m 6 E2 o zfio fi o 2 2m MQ OLQ m m 6 2 6 3H m m m E m 2 5 ETOG 6mdi5 o 31 5w 6 m m 8 E2 ii a ETO HS o z6=m=o 3a mo m m 6 Hz 4 2 mm ETO QEO OPZMO m O m d n mhn m m no amz #lnm a|| A HY OPZSO QH O a a I I m m #0 NZ 4J5 cm OsZAO N O mun I O m N H0 NZ 5 m Um O zHO m U mdhm .i mmo m "U mz bm w NTBN i m N #0 SHZ 5 mm I navwdwm 11...}--. mm M 6 NZ 3 aw 3 W993" H H 6 NZ 5 E w |||||||||||l m m m 4 cw B e o afi o 0 5 .m m E E m anan we M5 3138 96H 05 89 023 .6 55 n mm M 2 i=3? 2 51 2 86 :92am van 1323 Cd in .832 A8 56 2 G3 0 mnuwmwuou 96% 05 E8 3 0% 6 808 a mm M 53 8 0.538 uouomfi we 33538 5&3 9. 85838 5 83% oam un o nmbfi a mo uouumoh o5 womtmaou #033 62% 5 ow 2x con 63 033 bwwuwuoumahmnm wan m m 6 aomohgn CV Eo M2 5 van 038 236 3 30. .35 5 E fl Z/ 1 o M5 z mzoo m A60 96% 2: 88m 3 2% 3 505 Q mm M 598:3 "m .m 5% EZ Z\ m z o z m ZI 235 3.535% we o nmsmgo nmba a mo wauwmwaoo 96am 2: 60 3 2% 3808 a we co fimmoa 05 How $30.6 A A5 2:86 E3053 0 2:25am 5 "mm 2520 mm 22: m m m 6 wEQ Q n 2 7 J n m Lfiumovl o mz hm I: e W m QmoT 6 NZ 4 E 62 5 OFZAOOEHQO 3 am I "m0 m0 m 10 \ZNQWNOV 5-H 3 3! mm\-o o SaO m O wTDw 1 "m0 m0 m 6 n mo 0 26 5 0 2N 50 m 6 259 w 226 66 12 50 mo m 6 mz mo A -8 NS o vfio m o m 2: 3H0 HMO mm #0 .IHHZIQHQOE 3 1.8M o EO m=O 3&5 1 E0 E0 m 6 Lmo monswo m 5 "W0 1. 22666 21 5 o o m 6 fl l m 50 mo 6 amov o mmov m 6 z mov m 6 5:26 66 :3 56 m 6 226 5 0 @a E6 E5 m 6 256m ocfio m o Em mo mo m 6 i s 6 0 6 6 6 062 .m "m m E m 0385 EE H E m 2 3 m 2 5 EEQEE BEE (7) lower alkyl,

(8) hydIoXy-lower alkyl,

(9) di(lower alkyl)amino-lower alkyl,

(10) C cycloalkyl-lower alkyl,

(1 l phenyl-lower alkyl,

(12) lower alkyl-phenyl-lower alkyl,

( 13 w,w,w-trifiuoro-lower alkyl,

(14) pyridyl-lower alkyl,

(15) furyl-lower alkyl, and

(16) lower alkoxy-lower alkyl; R and R when lower alkyl can be linke dtogether to form with the nitrogen atom to which they are attached, a heterocyclic group;

R is a member selected from the group consisting of:

(a) halogen,

(b) lower alkyl,

() phenyl, and

(d) halo-phenyl;

R and R are similar or dissimilar and each is a member selected from the group consisting of:

(a) hydrogen,

(b) lower alkyl,

(c) when both represent lower alkyl they can be linked together to form a cyclic structure with the nitrogen atoms to which they are attached;

R is a member selected from the group consisting of:

(a) hydrogen,

(b) lower alkyl,

(c) phenyl-lower alkyl,

(d) naphthyl-lower alkyl,

(e) halo-phenyl-lower alkyl,

(f) lower alkyl-phenyl-lower alkyl,

(g) lower alkoxy-phenyl-lower alkyl,

(h) octahydro-l-azocinyl-lower alkyl,

(i) octahydro-l-azepinyl-lower alkyl,

(j) pyridyl-lower alkyl,

(k) hydroXy-lower alkyl,

(m) lower alkyl-phenyl,

(n) lower alkoXy-phenyl, and

(o) halo-phenyl;

R and R when lower alkyl can be linked directly to gether to form with the nitrogen atom to which they are attached a member selected from the group consisting of -8 membered rings; and R and R when lower alkyl can be linked together through a hetero atom selected from O and N to form with the nitrogen atom to which they are attached a member selected from the group consisting of 5-8 membered rings.

2. The process as claimed in claim 1, wherein R R and R are each hydrogen.

3. The process as claimed in claim 1,'wherein R and R are each hydrogen, and R is hydroxyethyl.

4. The process as claimed in claim 1, wherein R is amino and R is chloro.

5. The process as claimed in claim 1, wherein R is hydrogen and R is chloro.

6. The process as claimed in claim 1, wherein A is dimethylamino and R is chloro.

7. The process as claimed in claim 1, wherein R, R R and R each is hydrogen, and R is bromo, thus yielding (3-amino-6-bromopyrazinoyl)guanidine.

8. The process as claimed in claim 1, wherein R, R, R and R each is hydrogen and R is chloro, thus yielding (3-arnino-6-chloropyrazinoyl)guanidine.

9. The process as claimed in claim 1, wherein R is amino, R is chloro and R R and R each is hydrogen, thus yielding (3,5-diamino-6-chloropyrazinoyl)guanidine.

10. The process as claimed in claim 1, wherein R is dimethylamino, R is chloro, R R and R each is hydrogen, thus yielding (3-amino-5-dimethylamino-6-chloropyrazinoyl guanidine.

11. A process for the preparation of 3-amino-5 and/ or 6-substituted pyracinoic acid azides which comprises diazotizatiou of a 3-arnino-5 and/or 6-substituted-pyrazinoic acid hydrazide with aqueous nitrous acid in dilute mineral acid at from about ambient to about steam bath temperature.

12. The process according to claim 11 wherein the pyrazinoic acid hydrazide and pyrazinoic acid azide are of Structure I and II respectively:

N R \INH2 R iooNs N R T NHZ R1 ICONHNHz wherein R and R each have the meanings assigned to them in claim 1.

13. A compound of structural formula wherein R is a member selected from the group consisting of:

(1) hydrogen, (2) lower alkyl, (3) lower alkenyl, and R is a member selected from the group consisting of:

(1) hydrogen, (2) lower alkenyl, (3) C cycloalkyl, p y (5) lower alkyl-phenyl, (6) halo-phenyl, (7 lower alkyl, (8) hydroxy-lower alkyl, (9) di(lower alkyl)amino-lower alkyl, (10) C cycloalkyl-lower alkyl, l 1 phenyl-lower alkyl, (12) lower alkyl-phenyl-lower alkyl, (13) w,w,w-trifluoro-lower alkyl, (14) pyridyl-lower alkyl, (15) furyl-lower alkyl, and (16) lower alkoxy-lower alkyl; R and R when lower alkyl can be linked together to form with the nitrogen atom to which they are attached, a heterocyclic group; R is a member selected from the group consisting of:

(a) halogen, (b) lower alkyl, (c) phenyl, and (d) halo-phenyl. 14. 3-amino-6-chloropyrazinoic acid azide. 15. 3-amino-6,-bromopyrazinoic acid azide. 1d6. 3-amino-5-dimethylamino-6-chloropyrazinoic acid an e.

17. 3,S-diamino-6-chloropyrazinoic acid azide.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 260-2472 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION ne 11 3,527,758 Dated September 8, 1970 I Edward J. Cragoe, Jr. and James H. Jones It in certified that error eppeare in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

I In column 6, Table I, Example 10, in the column headed -1 "Analysis Found" change "6.0" to read -6.0land change "32.6" to read 32.63. In column 9, in the heading of Table II, correct the structure appearing under the second arrow to read as follows: R

H N-CN NR Column 10, Example 51, in the column headed "R" correct the structure to read as follows:

In column 12, Example 70, in the column headed "R" correct the structure to read as follows:

N Column 12, Example 78, correct the empirical formula to read C13H1l+ClN70 In column 13, in the columnar headings, change "R in the heading of the fifth column to read -R in Example 80, change the m.p. of product to read -l5360-; in Example 84, change the empirical formula to read --C ,,H ClN O-HCl. In column 14, Example 91, change the empirical formula to read C H Cl N O-; in Example 92, in the column headed "R"", correct the structure to read In column 15, in the columnar headings, change "R" in the heading of the fifth column to read -R in Example 104, in the column headed "R" delete the sign from the structure; and in Example 104, change the empirical formula to read C H ClN 0-. In column 1?, Claim 6, line 57, change "A" to read R-.

L. smmzu MD SEALED ml 5 @S Attach Edward 1!. mod-c. Jr. Attcsting Officer WW I. W, comisaio'ner of Pa 

